We studied mechanisms by which T cells recognize antigens with major histocompatibility complex (MHC)-encoded molecules, and applications to the design of synthetic vaccines for AIDS and cancer. We characterized a peptide fragment of the HIV-1 envelope recognized by CD8+ cytotoxic T lymphocytes (CTL) using a new system we developed in which CTL are stimulated by peptide bound to purified Class I MHC molecules on plastic. A 10-residue HIV peptide is a million times more active than the original 15-residue peptide in the absence of serum, and the longer peptide requires processing by angiotensin converting enzyme (ACE) in serum. We also showed that the Class I molecule plays two roles in CTL activation, one to present the peptide and the other probably to interact with CD8, as it requires only a conserved alpha 3 domain. The MHC molecule binding CD8 does not have to be the same one presenting peptide. We have shown that non-crossreactive CTL distinguish aliphatic from aromatic residues at a single position in this peptide. This finding led us to discover a way to induce broadly crossreactive CTL against multiple variants of HIV by stimulation with a chimeric peptide. CTL fine specificity correlated with specific receptor variable regions used. This CTL site, which also is a target of neutralizing antibodies, has been coupled to sites we identified that stimulate T helper cells in mice and humans of multiple MHC types, and the resulting candidate synthetic vaccine has been found to induce extremely high titers of neutralizing antibodies in mice, as well as specific CTL killing of HIV-1 envelope expressing cells. Also, an early diagnostic test is being developed. We also showed that schistosomiasis resulted in reduced clearance of concurrent vaccinia virus infection and decreased IL-2, interferon and CTL responses. This may account in part for the rapid spread of AIDS in Africa. We are also attempting cancer vaccines to induce CTL to mutant peptides corresponding to oncogene mutations that could kill tumor cells. We succeeded in inducing peptide-specific CTL that will kill tumor targets expressing a mutant p53 gene. Thus such mutant oncogene products, although not expressed on the cell surface, can serve as targets of specific cancer immunotherapy. Also, a CTL determinant of the hepatitis C virus has been found.